Mück W, Ochmann K, Rohde G, Unger S, Kuhlmann J
Bayer AG, Clinical Pharmacology, Wuppertal, Germany.
Eur J Clin Pharmacol. 1998 Feb;53(6):469-73. doi: 10.1007/s002280050408.
Cerivastatin is a novel, synthetic, highly potent 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor that effectively reduces serum cholesterol levels at very low doses. It is exclusively cleared from humans via cytochrome P450-mediated biotransformation (demethylation M1; hydroxylation M23) and subsequent biliary/renal excretion of the metabolites. The influence of concomitant administration of erythromycin, a potent CYP3A4 inhibitor, on cerivastatin bioavailability and pharmacokinetics was investigated.
Twelve healthy young male subjects received single oral doses of 300 microg cerivastatin alone or on the 4th day of a 4-day pre- and co-treatment with erythromycin 500 mg t.i.d. in a randomised, non-blind crossover study. Plasma and urine samples were analysed for cerivastatin and its major metabolites by validated specific high-performance liquid chromatography assays.
Cerivastatin was safe and well tolerated. No clinically relevant treatment-emergent changes in laboratory parameters were observed. The pre- and co-treatment with erythromycin 500 mg t.i.d. had a modest influence on cerivastatin clearance, leading to a mean increase in the maximum plasma concentration (Cmax) of 13% and a slightly increased terminal half-life (approximately 10%), resulting in a mean elevation of the area under the curve (AUC) of 21%; time to peak (tmax) remained unchanged. While the mean AUC of the metabolite M1 following the combined dosing was decreased by 60% compared with mono-dosing, the mean AUC of M23 exhibited an increase of approximately 60%. The respective Cmax results paralleled these pronounced effects, whereas the influence on mean terminal half-lives was small (i.e. for M23, an approximate 20% increase) or not observable (i.e. for M1).
Concomitant administration of erythromycin 500 mg t.i.d. affects, to a certain extent, the metabolism of cerivastatin, administered as a single oral dose of 300 microg, resulting in a slightly increased exposure of the parent drug and active metabolites which, however, does not need dose adjustment. In addition, the small increase in cerivastatin half-life does not predict an accumulation beyond steady state. The pharmacokinetic data for the major metabolites suggest that the M1 metabolic pathway is more sensitive to CYP3A4 inhibition than the parallel M23 pathway, supporting recent in vitro findings that further cytochrome P450 isozymes are differently involved in the metabolic pathways of cerivastatin.
西立伐他汀是一种新型的、合成的、高效的3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶抑制剂，能在极低剂量下有效降低血清胆固醇水平。它仅通过细胞色素P450介导的生物转化（去甲基化生成M1；羟基化生成M23）及随后代谢产物的胆汁/肾脏排泄从人体清除。研究了强效CYP3A4抑制剂红霉素的合并给药对西立伐他汀生物利用度和药代动力学的影响。
在一项随机、非盲交叉研究中，12名健康年轻男性受试者单独口服300微克西立伐他汀单剂量，或在红霉素500毫克每日三次、为期4天的预处理和合并治疗的第4天口服该剂量。通过经过验证的特异性高效液相色谱分析法分析血浆和尿液样本中的西立伐他汀及其主要代谢产物。
西立伐他汀安全且耐受性良好。未观察到实验室参数出现与临床相关的治疗中出现的变化。红霉素500毫克每日三次的预处理和合并治疗对西立伐他汀清除率有一定影响，导致最大血浆浓度（Cmax）平均升高13%，终末半衰期略有延长（约10%），曲线下面积（AUC）平均升高21%；达峰时间（tmax）保持不变。虽然合并给药后代谢产物M1的平均AUC与单剂量给药相比降低了60%，但M23的平均AUC升高了约60%。各自的Cmax结果与这些显著影响一致，而对平均终末半衰期的影响较小（即对于M23，升高约20%）或未观察到（即对于M1）。
红霉素500毫克每日三次的合并给药在一定程度上影响单剂量口服300微克西立伐他汀的代谢，导致母体药物和活性代谢产物的暴露量略有增加，不过这无需调整剂量。此外，西立伐他汀半衰期的小幅延长并不预示会在稳态以上发生蓄积。主要代谢产物的药代动力学数据表明，M1代谢途径比平行的M23途径对CYP3A4抑制更敏感，这支持了最近的体外研究结果，即其他细胞色素P450同工酶在西立伐他汀代谢途径中的参与情况有所不同。
